In this work we report the presence of intrametastatic smooth‐muscle iso‐α‐actin (SMA)‐expressing cells which appeared from the early stages of the hepatic metastasis process of intrasplenically injected B16 melanoma (B16M) cells. They formed a network of stromal cells among B16M cells, a very low percentage of them expressing desmin. In contrast, those parts of liver tissue unaffected by metastasis had perisinusoidal desmin‐expressing quiescent hepatic stellate cells (qHSC) which did not express SMA. Exposure of freshly isolated rat quiescent hepatic stellate cells (qHSC) to B16M cell‐conditioned medium (B16M‐CM) leads to a progressive increase (P < .01) in the number of SMA‐expressing cells, which was accompanied by a parallel reduction in the number of desmin‐expressing cells. In addition, B16M‐CM also contained chemotactic factor(s) which significantly (P < .01) increased (50%) in vitro qHSC migration and stimulated both [³H]thymidine and [³H]glucosamine uptake in qHSC. Moreover, B16M‐CM also significantly (P < .01) enhanced qHSC secretion of matrix metalloproteinase‐2 (MMP‐2), and unknown chemotactic factor(s) enhancing in vitro migration of B16M cells. The results suggest that B16 melanoma releases qHSC‐activating factors, which induce the appearance of metastasis‐infiltrating myofibroblasts by a paracrine mechanism. Such cells showed cytoskeletal alterations which are associated with enhanced proliferation, glycosaminoglycan synthesis, MMP‐2 secretion, and tumor‐chemotactic factor production. Thus, tumor‐activated qHSC may play an important role in melanoma cell motility and invasion during hepatic metastasis progression.